Two-dimensional (2D) nanomaterials have attracted great interests in biomedicine because of their unique structural feature and exciting physicochemical properties. The versatile platform of these nanosheets supports emerging biomedical applications, including bio-sensing, bio-imaging, drug delivery, cancer therapy, and tissue engineering. However, nanosheets like graphene-family nanomaterials could cause inflammation, edema, fibrosis, granuloma, etc.; cytotoxic effects of 2D nanomaterials greatly challenge those promising applications and have raised serious safety concerns.

Experimental studies have revealed that nanotoxicity depends on physical and chemical properties of nanomaterials (e.g., size, dosage, and surface characteristic). To thoroughly understand the cytotoxicity of 2D nanomaterials, molecular and thermodynamic insights into interactions between biological systems and 2D nanomaterials are necessary; but they are difficult to access using experimental techniques. This thesis presents our studies on the interaction of cell membranes with 2D nanosheets, using the molecular dynamics (MD) simulation that has been taken as a “computational microscope”.

In MD simulations, the cell membrane is simplified into lipid bilayer models. To thoroughly reflect the response of the cell membrane to nanosheets, and to carefully investigate molecular mechanisms, MD models of different resolutions and scales were used. First, a large scale coarse-grained (CG) MD model of a spherical liposome was constructed to study the impact of nanosheets on the overall morphology of cell membranes. Then, the morphological evolution of cell membranes under the effect of nanosheets was dissected into several basic molecule motions; and these crucial motions were further investigated using all-atom (AA) MD models, enhanced sampling methods, and thermodynamic analyses.

CG MD results demonstrate that the interaction morphology of lipid membranes and hydrophobic nanosheets depends on the size and the approaching orientation of nanosheets. As nanosheet size and orientation vary, the liposome could be locally deformed, split, and collapsed. According to the structural characteristics, the equilibrated interaction states were grouped into “insertion”, “corrugated insertion”, “split”, “corrugated sandwich”, and “collapse”. Of great importance is that these interaction states show great similarity with electron microscope images obtained in experiments, which bridges experiments and simulations and gave us confidence for further studies.

Scrutinizing MD trajectories, it was observed that the morphology evolution is driven by some basic molecule motions, including “nanosheet rotation”, “lipid extraction”, “lipid flip-flop”, and “lipid spreading”. Definitely, controlling these molecule motions is significant for the controlling of nanotoxicity, because some severely destructive interaction states may be avoided with effective strategies. Thus, some well-designed AA models and free energy calculations were used to further investigate insights in those molecule motions. For the “nanosheet rotation” motion, it was demonstrated that nanosheets thermodynamically prefer to be either perpendicular or parallel to lipid membranes, and the free energy barrier between them relies on the level of hydrophobicity of nanosheets. The “lipid extraction” motion was found sensitive to the phase state of lipid membranes; both decreasing temperature and the presence of cholesterols could effectively alleviate the destructive lipid extraction behavior.

Taken together, a comprehensive investigation of the interaction between lipid membranes and hydrophobic nanosheets was performed. On the one hand, multiscale results were revealed to bridge experiments and simulations. On the other hand, molecular mechanisms underlie the dynamic interaction activities were explored, which expands our knowledge on bio-nano interactions and provides implications for the mitigation of nanotoxicity. These works are expected to contribute to future studies on nanomedicine and nanotoxicology.